The intermitochondrial cement (IMC) is a prominent germ granule that locates among clustered mitochondria in mammalian germ cells. Serving as a key platform for Piwi-interacting RNA (piRNA) biogenesis; however, how the IMC assembles among mitochondria remains elusive. Here, we identify that Tudor domain-containing 1 (TDRD1) triggers IMC assembly via phase separation. TDRD1 phase separation is driven by the cooperation of its tetramerized coiled-coil domain and dimethylarginine-binding Tudor domains but is independent of its intrinsically disordered region. TDRD1 is recruited to mitochondria by MILI and sequentially enhances mitochondrial clustering and triggers IMC assembly via phase separation to promote piRNA processing. TDRD1 phase separation deficiency in mice disrupts IMC assembly and piRNA biogenesis, leading to transposon de-repression and spermatogenic arrest. Moreover, TDRD1 phase separation is conserved in vertebrates but not in invertebrates. Collectively, our findings demonstrate a role of phase separation in germ granule formation and establish a link between membrane-bound organelles and membrane-less organelles.

中文翻译：

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TDRD1 相分离驱动线粒体间水泥组装以促进 piRNA 生物发生和生育能力


线粒体间骨水泥 （IMC） 是一种突出的胚芽颗粒，位于哺乳动物生殖细胞中成簇的线粒体中。作为 Piwi 相互作用 RNA （piRNA） 生物合成的关键平台;然而，IMC 如何在线粒体中组装仍然难以捉摸。在这里，我们确定 Tudor 结构域包含 1 （TDRD1） 通过相分离触发 IMC 组装。TDRD1 相分离由其四聚体化卷曲螺旋结构域和二甲基精氨酸结合 Tudor 结构域的合作驱动，但独立于其固有无序区域。TDRD1 被 MILI 募集到线粒体中，并依次增强线粒体聚集并通过相分离触发 IMC 组装以促进 piRNA 加工。小鼠 TDRD1 期分离缺陷会破坏 IMC 组装和 piRNA 生物发生，导致转座子去抑制和生精停滞。此外，TDRD1 相分离在脊椎动物中是保守的，但在无脊椎动物中则不然。总的来说，我们的研究结果证明了相分离在胚芽颗粒形成中的作用，并在膜结合的细胞器和无膜细胞器之间建立了联系。